17-oxygenated estra-1, 3, 5 (10)-trien-4-ols and intermediates



3,098,852 Patented July 23, 1963 3,098,852 17-0XYGENATED ESTRA-1,3,5(10)-TREN-4-0LS AND INTERMEDTATES William F. Johns, Morton Grove, Ill., assignor to G. D. Searle 8; Co., Chicago, Ill., a corporation of Delaware No Drawing. Filed Feb. 2, 1962, Ser. No. 176,798 11 Claims. (Cl. 260-23955) This invention relates to l7-oxygenated estra-1,3,5 (10)-trien-4-ols, intermediates thereto, and processes for the preparation thereof. More particularly, this invention relates to (a) chemical compounds of the formula wherein Z represents a carbonyl or optionally-esterified hydroxymethylene radical, and (b) means whereby these compounds can be produced.

Among the esterified hydroxymethylene radicals contemplated Z in the foregoing formula, alkanoyloxymethyh ene radicals are preferredespecially those in which the alkanoyl constituent is of lower order, i.e., has the formula CO-lower alkyl By lower alkyl is meant methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 'hexyl, isohexyl, and like monovalent, saturated, acyclic, :straightor branched-chain, hydrocarbon groupings of empirical formula proceeds by oxidizing l7fl-hydroxyestr-4-en-3-one with hydrogen peroxide in the presence .of osmium tetroxide to give 45,5,17fl-trihydroxy-5B-estran-3-one, which is reacted with 1,2-eth-anedithiol to give the corresponding ethylenethioketa-l. The ketal is reduced to 5/i-estrane-4B, 5,17B-triol with activated Raney nickel, and the hydroxyls at 4 and 17 therein are oxidized to c-anbonyls with chronium trioxide-pyridine complex. Bromine in acetic acid catalyzed by a trace of hydrogen bromide serves to convert S-hydroxy-SB-estranel,17-dione to the 3 bromo derivative, from which 4-hydroxy-estra-1,3,S(l0)-trine-l 7 2 one is obtained by heating with lithium chloride in N,N- dimethylformamide.

Alternatively, estra-4-en-17/8-ol is oxidized to the 40:, Soc-epOXide with perbenzoic acid; and the epoxide is hydrolyzed in the presence of fi-toluene-sulfonic acid to give 5a-es-tr'ane-4B,5,l7/3-triol. The hydroxyls at 4 and 17 therein are oxidized to carbonyl-s with chromium trioxidepyridine complex, whereupon 3-monobromination is effected with bromine in acetic acid catalyzed by hydrogen bromide and the 3-bromo-5-hydroxy-5a-estrane-4,17-dione thus obtained is converted to 4-hydroxyestra-l,3,5 (10)-trien-17-one v-ia lithium chloride in N,N-dimethy-lformamide.

Still another route to the same product comprises alcohlysis of 4u,S-epoxy-5u-estran-l75-01 with aqueous ethanol to give 4/3-ethoxy-5a-estrane-5,17,8-diol, followed by chromium trioxide-pyridine complex oxidation of the l7-hydroxyl therein to carbonyl. The resultant compound is converted with boron trifiuoride etherate to 50- estrane-4,l7- dione which, in turn, is 3,5-dibrominated with bromine in acetic \acid catalyzed by hydrogen bromide. The dibromo compound, on heating with 2,4,6-v trimethylpyridine, affords 4-hydroxyestra-1,3,5 10) -trien- 17-one. As a variation of this procedure, the Sea-estIane- 4,17-dione intermediate in the foregoing sequence can be obtained from 4,17fi-dihydroxyestr-4-en-3-one via ketalization with 1,2-etl1anedithiol, followed by reduction of the ketal to 5u-estrane-4B,l7fi-diol with activated Raney nickel and oxidation of the diol to the dione with chromium trioxide-pyn'dine complex.

Reduction of 4-hydroxyestra-1,3,5(10)-trien-1'7-one with sodium borohydride affords estra-1,3,5(10)-triene- 4,17B-diol.

The l7fl-alkanoyloxyestra- 1,3,4 l-O) -trien-4-ols hereof eventuate by reducing 17,8-hydroxy-5B-estrane-3,4-dione 3-ethyleneketal with acetonic Raney nickel to give hydroxy-Sa-estran-4-one, which then is esterified ad libitum with an alkanoic acid anhydride in pyridine solution and thereupon is 3,5-dibrominated with bromine in acetic acid catalyzed by hydrogen bromide. The di'bromo compound, on heating with 2,4,6-trimethylpyridine, affords the corresponding 17B-alkanolyestra-1,3,5 10) -trien-4-ol.

Reductive cleavage of the 17-ester linkage in the subject 17B-alkanoyloxyestra-l,3,5(10)-trien-4-ols with lithium aluminum hydride provides an alternative route to estra-1,3,5 10) -triene-4, 17B-diol.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their preparation. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees Centigrade and relative amounts of materials in parts by weight, except as otherwise noted. Specific rotations are referred to the D line .of sodium.

Example 1 A. 45,5,17,8-trihydroxy-SB-estran-3-0ne.-To a solution of 50 parts of 17fi-hydroxyestr-4-en-3-one in 1750 parts of ether at 0 is added 56 parts of aqueous 30% hydrogen peroxide, followed by 1 part of osmium tetroxide.

3 The resultant mixture is allowed to stand at room temperature for 18 hours, then consecutively diluted with 400 parts of ice water and-very slowly-40 parts of aqueous 1% potassium hydroxide. The ether phase is separated, washed with water, and stripped of solvent by distillation. The residue is chromatographed on silica gel, using benzene and ethyl acetate in increasing amounts of the latter as developing solvent. From an eluate comprising 25% ethyl acetate in benzene, upon distillation of the solvent and recrystallization of the residue from a mixture of acetone and hexane, is obtained 4 3,5,17B-trihydroxy-5fl-estran-3-one melting at 184-494".

B. 45,55,175 trihydroxy 5e estran 3 one ethylenethikeml.To a solution of approximately 15 parts of 4,6,5,-17B1trihydroxy-55-estran-3-one in 200 parts of acetic acid and approximately 6 parts of 1,2-ethanedithiol is added 9 parts of boron trifluoride etherate. The resultant mixture is allowed to stand at room temperatures for 2 /2 hours, whereupon :10 parts of solid potassium acetate is mixed in, followed by 800 parts of water. The precipitate which forms is filtered off and extracted into chloroform. The chloroform extract is consecutively washed with water and aqueous potassium bicarbonate, then dried over anhydrous sodium sulfate and finally stripped of most of the solvent by distillation. The concentrate thus obtained is chromatographed on silica gel using benzene and ethyl acetate in increasing amounts of the latter as developing solvent. From an eluate comprising 20% ethyl acetate in benzene, on distillation of solvent and recrystallization of the residue from acetone, is obtained 4,8,5,17B-trihydroxy-B-estran-Zi-one ethylenethioketal melting at 192195 and further characterized by a specific rotation of +l8.

C. 5B-estrane-4[3,5,17/3-tri0l.-A mixture of 40 parts or activated Raney nickel and a solution of 11 parts of 4 8,5,17B-trihydroxy-5fl-estran-3-one ethylenethioket-al in 800 parts of 95% ethanol is maintained with agitation at the boiling point under reflux for 20 hours. It is then filtered, and the filtrate is stripped of the bulk of the solvent by distillation. The concentrate thus obtained is chromatographed on silica gel, using benzene and ethyl acetate in increasing amounts of the latter as developing solvent. From eluates comprising upwards of 40 ethyl acetate in benzene, on evaporation of solvent and recrystallization of the residue from acetone, is obtained 5,8- estrane-4fi,5,l7[3-triol melting at 182-184 and further characterized by a specific rotation of +23 7 l). 5-hydroxy-5fl-estrane-4J7-di0ne.--To a slurry of 20 parts of chromium trioxide in 4-00 parts of pyridine is added a solution of 7 parts of 5fi-.estrane-4[3,5,17ptriol in 200 parts of pyridine. The resultant mixture is maintained at room temperatures with agitation ior 20 hours, then partitioned between water and ether. The ether phase is separated, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from a mixture of acetone and hexane, affords 5 hydroxy-5,6-estrane-4,17-dione melting at 185- 188" and further characterized by a specific rotation of +28".

E. 3 bromo 5 hydroxy 5B estrane 4,17 di ane.To a solution of 500 parts of S-hydroxy-Sfl-estrane-4,17-dione in 25,000 parts of acetic acid containing 4 parts of hydrogen bromide is added, at and during 20 minutes, a solution of 960 parts of bromine in 12,000 parts of acetic acid. The resultant solution is diluted with 50,000 parts of water, and the precipitate thrown down is collected on a filter and washed thereon with water. The material thus obtained, dried in air and thereupon recrystallized from a mixture of acetone and hexane, is 3-bromo-5 hydroxy-5fl-estrane-4,17-dione melting at 186-188 and having a specific rotation of +104.

F. 4hydr0xyestra-1,3,5(10) -trien-1 7-0ne.A solution of 18 parts of 3promo-5 hydroxy-Sfl-estranel,17-dio-ne (preparable by the procedure of the foregoing part B of this example) and 200 parts of lithium chloride in 2900 parts of N,N-dimethylform=amide is heated at the boiling point under reflux in an atmosphere of nitrogen for 2 /2 hours. It is then cooled and diluted with 2 volumes of water. The crystalline precipitate which forms is filtered ofi and recrystallized from a mixture or acetone and petroleum ether to give 4-hydroxyestra-l,3,5(10)-trien- 17-?ne melting at 270-275 The product has the formu a Example 2 Estra-1,3,5(10)-triene-4,17/8-diol.To a solution of 5 parts of 4-hydroxyestra-1,3,5(10)-trien-17-one in 1600 parts or methanol is added a solution of 1 part of sodium borohydride in parts of water. The resultant solution is maintained with agitation at room temperatures for 4 hours and then consecutively diluted with "100 parts of acetice acid and 1000 parts of Water. The precipitate thrown down is filtered off and recrystallized from a mixture of acetone and petroleum ether to give estra- 1,3,5 (l0)-triene-4,17fl-diol melting at 200-202. The product has the formula Example 3 A. 4a,5-epoxy-5o-estran-17fi-ol.To a solution of 87 parts of estr-4-en-17/8 ol in 1490 parts of chloroform is added a solution of 63 parts of perbenzoic acid in approximately 1200 parts of benzene. The resultant solution is allowed to stand tor 65 hours at room temperatures, whereupon it is mixed with approximately 2 volumes of water. The organic solvent phase is separated and thoroughly Washed with aqueous 2% potassium hydroxide. It is then stripped of solvent by distillation; and the residue is crystallized from petroleum ether, alfo-rding 4u,5-epoxy- Soc-CSUFElLl-17B-0l rneltin-g at -137 and with a specific rotation of +43 B. 5a-estrane-4,B,5,17 3-tri0l.To a solution of 30 parts of 4oz,5-epoxy-5a-estran-17fi-ol in 277 parts of acetone is added a solution of 1 part of p-toluenesulfonic acid in 30 parts of water. The resultant solution is maintained with agitation at room temperatures for 30 minutes and then diluted with excess aqueous potassium bicarbonate. Insoluble solids, filtered off and recrystallized from acetone,

aiiord 5a-estrane-4fi,5,17,8-triol melting at approximately due, recrystallized from acetone, affords 5-hydroxy-5uestrane-4,17-dione melting at 228-230 D. 3-br0m0-5-hydroxy-5a-estrane-4,17 dine.To a solution of 56 parts of -hydroxy-5a-estrane-4,l7-dione in 2500 parts of acetic acid is added, at during 10 min utes, a solution of parts of bromine in 840 parts of acetic acid. Excess aqueous sodium thiosulfate is thereupon introduced, followed by 5000 parts of Water. The precipitated solids are collected on a filter, dried in air, and recrystallized from a mixture of acetone and petroleum ether to give 3-bromo-5 hydroxy-5m-estrane-4,17-dione melting at 175178 (with decomposition).

E. 4-hydr0xyestra-l,3,5 (10)-trien-17-0ne.A solution of 62 parts of 3 bI'OmO-S-hYdI'OXY-SOt-EStIEIlfi-l,17*dl0ne (preparable by the procedure of the foregoing part I) of this example) and 200 parts of lithium chloride in 4750 parts of -N,N-dimethylformamide is heated at the boiling point under reflux in an atmosphere of nitrogen for 2 hours. it is then cooled and poured into 3 volumes of water. The resultant mixture is extracted with chloroform. The chloroform extract is stripped of solvent by distillation; and the residue is chromatographed on silica gel, using benzene and ethyl acetate in increasing amounts of the latter as developing solvent. From an eluate comprising 5% ethyl acetate in benzene, on distillation of solvent and recrystallization of the residue from a mixture of acetone and petroleum ether, is obtained 4-hydroxyestra-1,3,5(10)-trien-17-one melting at 270-275 Example 4 A. 4fl-ethoxy-Suwstrane-SJ7}8-di0l.--A solution of parts of 4m,5-epoxy-5a-estran-17 8 01 in 79 parts of 95% ethanol and 20 parts of water is heated at the boiling point under reflux for 10 minutes and then allowed to cool to room temperature. Approximately 2 hours later the solution is stripped of solvent by distillation; and the residue, crystallized from a mixture of acetone and ether, affords 4fl-ethoxy-5oz-estrane-5,17,6-diol.

B. 413-2thoxy-S-hydroxy-Six-estran-I 7-one.To a slurry of 5 parts of chromium trioxide in 200 parts of pyridine is added a solution of 3 parts of 4fi-ethoxy-5westrane-5,17,8- @1011. The resultant mixture is maintained with agitation at room temperatures for 2 hours and then partitioned between water and ether. The ethereal phase is separated, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from a mixture of acetone and hexane, affords 4fi-ethoxy-5-hydIOXY-SOt-fiSlIHIl-l7r0fl6.

C. 5a-estrane-4J7-dione.To a solution of approximately 1 part of 4B-ethoxy-5-hydroxy-5et-estran-17-one in 44 parts of dry benzene is added approximately 6 parts of boron trifluoride etherate. The resultant mixture is maintained at room temperatures for 20' hours, then diluted and mixed with excess aqueous potassium bicarbonate. The benzene phase is separated, consecutively washed with aqueous potassium bicarbonate and water, \dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized ttrom a mixture of ether and petroleum ether, affords 5u-estrane-4,17-dione melting at approximately 134-135 and having a specific rotation of +119.

D. 3,5-dibromoestrane-4,17-dione.To a solution of 400 parts of 5a-estrane-4,17-dione in 30,000 parts of acetic acid containing 4 parts of hydrogen bromide is added, at 15 during 15 minutes, a solution of 1900 parts of bromine in 12,000 parts of acetic acid. Suflicient aqueous sodium thiosulfate is then introduced to discharge a slight excess or bromine, whereupon the precipitate which has formed is filtered off and dried in air. The product thus isolated is 3,5 -dibromoestrane-4, l7-dione.

E. 4-hydr0xyestra-1,3,5(10)-trien-17-0ne.A mixture of 1 part of 3,5-dibromoestrane-4,17-dione (preparable by the procedure of the fioregoing part D of this example) and 27 par-ts of 2,4,6-trimethylpyridine is heated at the boiling point under reflux for 30 minutes, then cooled and Example 5 A. 17 8 hydroxyestran-3,4-dione-3-ethylenethi0ketal.- To a solution of approximately 10 parts of 4,17p-dihydroxyestr-4-en-3-one in 17 parts of 1,2-ethanedithiol and 30 parts of acetic acid is added 7 parts of boron trifluoride etherate. The resultant mixture is maintained at room temperatures for 10 minutes, then diluted with 72 parts of methanol. The insoluble solids which result are filtered out and recrystallized from chloroform, affording 17(3- hydroxy-Sfl-estran-3,4-dione 3-ethylenethioketal melting at 282-286" and further characterized by a specific rotation of -68". From the mother liquors, on further dilution with water, an additional precipitate is obtained. This material, recrystallized from acetone, is 17fi-hydroxy-5aestran-3,4dione 3-ethylenethioketal melting at 212215 and having a specific rotation of 120.

B. 5-estrane-4,B,17,8-diol.A mixture of 10 parts of activated Raney nickel and a solution of 1 part of 17/3- hydroxy-Sti-estran 3,4 dione 3-ethylenethioketal in parts of ethanol is heated at the boiling point under reflux with agitation for 14 hours. It is then filtered, and the filtrate is concentrated to a semicrystal'line residue. Recrystallization of the residue from a mixture of ether and petroleum ether affords 5a-estrane-4B,17p-diol melting at 157159 and having a specific rotation of +29.

C. 5u-estrane-4,17-dione.-To a slurry of 10 parts of chromium trioxide in 200 parts of pyridine is added a solution of 7 parts of 5a-estrane-4fi,17B-dio1 in parts of pyridine. The resultant mixture is allowed to stand at room temperatures overnight. It is then diluted with water, and the mixture thus obtained is extracted with ether. The ether extract is washed with Water, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from a mixture of acetone and petroleum ether, aflords 5a-estrane-4,l7-dione melting at approximately 134135 and having a specific rotation of +119".

Example 6 i A. 17fi-hydr0xy-5a-estrai1-4-0ne.A mixture of 60 parts of activated Raney nickel and a solution of 15 parts of 17,8hydroxy-5,8-estran-3,4 dione 3-ethylenethioketa-l in 480 parts of 95% ethanol and 320 parts of acetone is heated at the boiling point under reflux with vigorous agitation for 4 hours. It is then filtered, and the filtrate is stripped of solvent by distillation. The residue is chromatographed on silica :gel, using benzene and ethyl acetate in increasing amounts or the latter as developing sol vent. From an eluate comprising 3% ethyl acetate in benzene, on distillation of solvent and recrystallization of the residue from a mixture of acetone and petroleum ether, there is obtained 17fi-hydroxy-5a-estran-4-one melting at 184-1 87 and further characterized by a specific rotation of +24".

B. l7B-acet0xy-5a-estran-4-0ne.-A solution of approximately 1 part of 17fi-hydroxy-5a-estran-4one in 40 parts of pyridine and 20 parts of acetic anhydride is heated at around 100 for 15 minutes, then cooled and diluted with 3 volumes of Water. The crystalline material thrown down is filtered ofi, dried in air, and recrystallized from a mixture of acetone and petroleum ether to give 17 ,B-acetoxy-Sa-estran-4 one melting at approximately l41.

C. 17B-acel0xy-3,5-dibrom0estran-4-one.-To a solution of 400 parts of 17fl-acetoxy-5a-estran-4-one in 30,000 parts of acetic acid containing 4 parts of hydrogen bromide is added, at 15 during 15 minutes, a solution of 1440 parts of bromine in 18,000 parts of acetic acid. Sufficient aqueous sodium thiosulfate is then introduced to discharge excess bromine, followed by 100,000 parts of water. Insoluble solids are filtered off, dried in air, and recrystallized from a mixture of acetone and petroleum ether to give 17,8-acetoxy-3,5=dibromoestran-4-one melting at approximately 169 (with decomposition).

D. l7,8-acetxyestra-1,3,5(1O)-trien-4-0l.-A solution of approximately 1 part of 17fi-acetoxy-3,S-dib-romoestran-4-one (preparable by the procedure of the foregoing Part C of this example) in 27 parts of 2,4,6-trimethylpyridine is heated at the boiling point under reflux for 30 minutes, then cooled and diluted with excess dilute hydrochloric acid. The resultant mixture is extracted with benzene. The benzene extract is Washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from a mixture of acetone and petroleum ether, =aifords l7 8-acetoxyestra-1,3,5(10)-trien-4-ol melting at 199-201". The product has the formula I OH Example 7 Bum-1,3,5(10)-triene-4,17fl-diol.To a solution of 4 parts of lithium aluminum hydride in 710 parts of ether is added, during 10 minutes, a solution of 4 parts of 17pacetoxyestra-1,3,5(10)-trien-4-ol in 710 parts of ether. The resultant solution is allowed to stand at room temperatures for 30 minutes, then consecutively diluted with 36 parts of ethyl acetate, 100 parts of water, and 100 parts of 7% hydrochloric acid. The mixture thus obtained is extracted with ethyl acetate. The acetate extract is dried over anhydrous sodium sulfate and stripped of solvent by distillation. The residue, recrystallized from a mixture of acetone and petroleum ether, affords estra- 1,3,5(10)-triene-4,17fi-diol melting at ZOO-202.

What is claimed is:

1. A compound of the formula wherein Z represents a member of the group consisting of carbonyl, B-hydroxymethyl'ene, iand B-(lower alkanoyloxy)methylene radicals.

4-hy-droxyestra- 1,3,5 10) -trien-17-one. Estra-1,3,5(10)-triene-4,17,6-diol. 17B-acetoxyestra-l,3,5(10)-trien-4-ol. 4,8,5,17 8-trihydroxy-5fi-estran-3one. 4a,5-epoxy-5u-estran-175ml,

7. A compound of the formula wherein Z represents a member of the group consisting of fl-hydroxymethylene and carbonyl radicals.

8. 5a-estrane-4,17-dione.

10. A compound selected from the group consisting of a compound of the formula 11. A compound selected from the group consisting of a compound of the formula and a compound of the formula Noreferences cited. 

1. A COMPOUND OF THE FORMULA 